Pharmaceutical composition comprising certain {60 {62 -unsaturated ketones

ABSTRACT

The invention relates to a pharmaceutical composition comprising a diluent and an effective amount of certain Beta , Beta bis(trifluoromethyl or chlorodifluoromethyl)- Alpha , Beta Unsaturated ketones and a method of applying these compositions to animals for the purpose of causing disability.

United States Patent Langkammerer 1 Sept-5, 1972 [54] PHARMACEUTICAL COMPOSITION [56] References Cited COMPRISING CERTAIN 043- UNSATURATED KETONES UNITED STATES PATENTS 2,889,246 6/1959 Harker .......l67/46 A [72] Invent gf g' Langkammm" 3,068,274 12/1962 McCall ..-..;167/46 A 3,076,015 1/1963 McCall et al ..l67/46 A X [73] Assignee: E. l. du Pont de Nemours and Com- 3,238,090 3/1966 Szabo ..l67/22' M pany, Wilmington, Del. Primary Examiner-Leland A. Sebastian [22] Filed. May 17, 1966 Attorney Herbert w Larson [21] Appl. No.: 551,843

' ABSTRACT [5 2] U.S. Cl. ..424/275, 424/285, 424/331 The invention relates to a pharmaceutical composition [51] Int. Cl. ..A0ln 9/00, A01n 9/12, A0ln 9/20 comprising a diluent and an effective amount of cer- [58] Field of Search ..l67/46 A, 47, 22 K, 22 M; tain Bfi-bisflrifluoromethyl or chlorodifluoromethyD- a,B-Unsaturated ketones and a method of applying these compositions to animals for the purpose of causing disability.

2 Claims, No Drawings PHARMACEUTICAL COMPOSITION COMPRISING CERTAIN aB-UNSATURATED KETONES This invention relates to a, B-unsaturated ketones.

More specifically, this invention refers to B, B- bis(trifluoromethyl)-a, B-unsaturated ketones, compositions employing them and a process of applying these compounds to animals for the purpose of causing disability.

The compounds of this invention possess the following structural formula:

wherein R is t-butyl, phenyl, methyl-, cyano-, fluoro-, chloro-, bromo-, methoxyor nitro-substituted phenyl, naphthyl, chloronaphthyl, furyl, thienyl, B-phenylethenyl;

R is hydrogen or alkyl of one through eight carbon atoms;

R and R can be combined to form cyclopentyl, a tetrahydronaphthalene, 7-nitrotetrahydronaphthalene or norbornane; and

X and Z are separately either chlorodifluoromethyl or trifluoromethyl.

The compounds of formula (1) wherein R is hydrogen are preferred because of high incidence of animal disability at low dose rates.

Use

The compounds of formula (1) cause irritation to animals, affecting the eyes and upper respiratory tract. in aerosols the compounds could be used in riot control, rodent control or burglar alarm systems. Preparation Compounds of the present invention are made by starting with wherein R, R, X and Z have the same meaning as above.

The compounds of formula (2) are treated with thionyl chloride in di-methylformamide or are dehydrated by heating with acetic anhydride.

Composition Compounds of this invention can be administered alone but are generally contained in a composition with a pharmaceutical carrier or diluent selected on the basis of the chosen route of administration and standard pharmaceutical practice. If the chosen route of administration is orally, the compounds can be administered in the form of tablets or capsules containing such excipients as starch, milk, sugar, clays and the like. Compounds can also be administered orally in the form of elixirs or oral suspensions containing coloring and flavoring agents.

If administered parenterally, the composition can take the form of sterile aqueous solutions containing solutes such as saline, or glucose in sufficient quantity to make the solution isotonic. For intramuscular administration, compositions of the compound of this invention can be prepared in an oil base such as peanut or sesame oil.

If administered as a vapor or spray application through the mouth or nasal passages a composition will contain some acceptable liquid such as water, acetone or alcohol.

Dosage The amount of active ingredient in the compositions will vary from 0.005 to 95 percent by weight or even higher. Exact concentration of active ingredient will depend on the mechanism used for administration and will be easily understood by one knowledgeable in pharmaceutical application rates. The effective pharmaceutical dose of an intraveinous treatment is 0.5 to 5 milligrams of active compound per kilogram of body weight of the animal recipient. Rates of over 56 milligrams per kilogram of body weight will kill percent of the animal recipients.

An effective pharmaceutical dose of an inhalation treatment is 0.5 to 2 milligrams per liter of air at exposure of one minute. More than 100 milligrams per liter of air at exposure of 1 minute is required to kill 50 percent of the animal recipients.

The following additional examples are provided to more clearly set forth the invention. All parts are by weight unless otherwise indicated.

EXAMPLE 1 A Hastelloy C autoclave with a 200 ml. capacity is charged with 60 parts of acetophenone, then evacuated and cooled in a liquid nitrogen bath and charged with parts of hexafluoroacetone. The autoclave is sealed, heated at for 8 hours and then cooled and opened.

- The 141 g. of liquid remaining is distilled in a spinning band fractionating column to give 133.4 parts 93 percent yield) of 3-hydroxy-l-phenyl-4,4,4-trifluoro-3- trifluoromethyl-l-butanone boiling at 6l64C. at 0.08 mm. of mercury and with a refractive index of n l.44l0.

anal. calcd. for C H F O found:

anal. calcd. for C I-I F O: found:

Mice are treated by aerosol exposure to the test compound in the following manner: The compound is administered as an aerosol into a 2.8 liter chamber. The exposure chamber consists of a 2.8 liter bell jar over a nebulizer inserted through the floor of the chamber.

Mice are exposed for five minutes to 200 micrograms (1,000 Ct). The compound is dissolved in acetone and, during a span of twenty seconds, the compound is sprayed up into the chamber. No further air is transferred into or out of the chamber during the 5 minute exposure.

After this exposure, irritant activity is observed in all mice exposed, but not in controls exposed to acetone alone. Irritant activity can be described as the presence of one or more of the following reactive signs:

l-lyperemia of the nose, ears, and tail Salivation Ptosis Dyspnea Decreased locomotor activity Blinking Hunched posture Face pawing.

Gerbils are treated to the test compound by exposure in a 16 liter static chamber in the following manner: The compound is dissolved in methylene chloride. The resulting colorless solution is sprayed into the chamber through a port in the bottom, animals being maintained around the entrance port. The spray impinges on the top of the chamber, then slowly settles down on the gerbils in the form of a vapor. The exposure time is one minute. A concentration which shows irritant activity is 2,000 micrograms. The gerbils are removed from the chamber at the end of one minute exposure. Characteristic symptoms in the gerbil after exposure to irritants are the following:

Abnormal gait, consisting of rubbing the nose on the floor while walking about (shovelnosing) Ptosis F ace pawing Dyspnea Rats are treated in a manner similar to gerbils, and show the following symptoms in addition to the above:

Salivation Lacrimation Piloerection Hyperactivity EXAMPLE 2 The Hastelloy C autoclave used in Example 1 is charged in the same way with- 82.5 parts of 3- nitroacetophenone and 90 parts of hexafluoroacetone, sealed, and heated at 160 C. for 8 hours. After cooling and venting the 155 parts of liquid remaining is distilled in a spinning band fractionating column to give 124.2 parts (75 percent yield) of 3-hydroxy-l-(3-nitrophenyl)-4,4,4-trifluoromethyl-l-butanone boiling at 1 17 C.

at 0.17 mm. of mercury and with a refractive index of n 1.4735.

anal. calcd. for C H F NO found:

A flask attached to a reflux condenser with a calcium chloride tube at the top and a magnetic stirrer is charged with 15 parts of the 3-hydroxy-1-(3-nitrophenyl)-4,4,4-trifluoromethyl-l-butanone prepared above and with 40 parts of acetic anhydride and refluxed for 16 hours with stirring. Fractional distillation of the liquid gives 10.7 parts of l-(3-nitrophenyl)-4,4,4- trifluoro-3-trifluoromethylbutene-2-one-l with a boiling point of 94-95 at 0.3 mm. of mercury with a refractive index of n 'l .4757.

anal. calcd. for C H F NO C, 42.1; H, 1.6;

found: C, 41.7; H, 1.7;

Squirrel monkeys are exposed to the test compound in the following manner: The compound is dissolved in methylene chloride, forming a colorless solution. The solution is forced through a nebulizer, and thence to a turbulence bulb, where the compound forms particles distinct from the vapor of the solvent. Both solute and solvent vapors are blown into a 50 liter chamber containing two monkeys. The animals are exposed to a concentration of 2,000 micrograms for one minute, with constant flow of compound maintaining this concentration (dynamic chamber).

At the end of the exposure, the monkeys are removed from the chamber and caged in well ventilated quarters. Characteristic reactive signs seen in the The following compounds are made in the manner of the compounds of Examples 1 and 2 by substituting the appropriate starting materials to form compounds of the formula:

The meaning of R, R, X and Z is found in the Table.

The product compounds are formulated and applied to animals in like manner to provide like results.

TABLE Ex. No. R R X Z Product Properties 3 (CH hC H CF: CF 5,5dimethyl- 1,1,l-trifluoro EXAMPLE 35 anal. calcd. for C H F O 4 Found: 4

c, 3.1;H,3.6; C, 2.6; 1-1, 3.6

3-[( l-Hydroxy-2,2,2-trifluorol -trifluoromethyl)- ethyl1-2-norbornanone (27.6 parts), parts of dry xylene, 23.2 parts of thionyl chloride and 0.4 parts of dimethylformamide are refluxed for three days with stirring and protected from atmospheric moisture. Distillation gives 15.3 parts (60 percent yield) of 3- [2,2,2-trifluorol -trifluoromethyl)ethylidene]- bicyclo(2.2.l)-heptane-2-one with a boiling point of 9497 at 12 mm. Hg. and a refractive index of n l.4203.

anal. calc'd. for C H F O:

Found:

EXAMPLE 36 anal. calcd. for C H, Cl F O: C, 41.2; H, 2.8;

Cl, 2.44 found: C, 41.3; H, 3.4;

EXAMPLE 37 a-Tetralone and hexafluoroacetone as intermediates substituted in like amount by weight for the intermediates of Example 35 give 2-(2,2,2-trifluoro-lhydroxyl-trifluoromethyl )ethyl-3 ,4-dihydro-1(2H)- naphthalenone, melting point 7475 C. which on dehydration gives 2-(hexafluoroisopropylidene)-3,4- dihydro-l(2H)-naphthalenone, boiling point 68C. at 0.1 mm. Hg. and refractive index n l .4826.

anal. calc'd. for C H F O: C, 53.0; H, 2.7 C, 52.8;1-1 2.7

EXAMPLE 3:;

7-Nitro-l-tetralone and hexafluoroacetone as intermediates substituted in like amount by weight for the intermediates fExam le 35 ive 2- -h -3,3,3- tri-fluQrO-Z-trifluorome thyl)efi'iyl]-7 ii%ro y dihydro-l(2H)-naphthalenone, melting point I40-2 C. (Analysis calculated for C, H F NO,: C, 43.7; H, 2.5; N, 3.9. Found: C, 44.2; H, 2.8; N, 4.3), which on dehydration gave 7-nitro-2-hexafluoroisopropylidene- 3 ,4-dihydro- 1 (2H )-naphthalenone, melting point l28l 30 C.

anal. calcd. for C,;,H F,,NO;,: C, 46.0; H, 2.1;

N, 4.1 found: C, 46.1; H, 2.2;

I claim:

l. A pharmaceutical composition comprising a pharmaceutically acceptable diluent and an effective pharmaceutical dose of a compound of the formula:

wherein R is selected from the group consisting of t-butyl, phenyl, methyl-, cyano-', fluoro-, chloro-, bromo-, methoxy, nitro-substituted phenyl, naphthyl, chloronaphthyl, furyl, thienyl, B-phenylethenyl;

R' is selected from the group consisting of hydrogen and alkyl of one through eight carbon atoms;

R and R are joined to form a radical selected from the group consisting of cyclopentyl, atetrahydronaphthalene, 7- nitrotetrahydronaphthalene and norbornyl;

X is selected from the group consisting chlorodifluoromethyl and trifluoromethyl; and

Z is selected from the group consisting chlorodifluoromethyl and trifluoromethyl.

2. A method of producing analgesic effects in animals comprising applying to a warm-blooded animal an effective pharmaceutical dose of a compound of the formula:

X of 

2. A method of producing analgesic effects in animals comprising applying to a warm-blooded animal an effective pharmaceutical dose of a compound of the formula: wherein R is selected from the group consisting of t-butyl, phenyl, methyl-, cyano-, fluoro-, chloro-, bromo-, methoxy-, nitro-substituted phenyl, naphthyl, chloronaphthyl, furyl, thienyl, Beta -phenylethenyl; R'' is selected from the group consisting of hydrogen and alkyl of one through eight carbon atoms; R and R'' are joined to form a radical selected from the group consisting of cyclopentyl, Alpha -tetrahydronaphthalene, 7-nitrotetrahydronaphthalene and norbornyl; X is selected from the group consisting of chlorodifluoromethyl and trifluoromethyl; and Z is selected from the group consisting of chlorodifluoromethyl and trifluoromethyl. 